1. Field of the Invention
The invention relates to methods and implantable devices for dispensing one or more therapeutic agents at a surgical site. More particularly, the invention relates to devices and methods for controllably delivering therapeutic agents to an orthopaedic surgical site that requires the implantation of a prosthesis within the site.
2. Prior Art
Biodegradable materials are used in medicine for a variety of purposes including drug delivery devices and as aids in tissue repair. The physical and chemical properties of such materials can vary as in the case of different polymeric materials, e.g., melting point, degradation rate, stiffness, etc. The variability in physical and chemical properties of biodegradable polymeric materials allows biodegradable implants made from such materials to be tailored to suit specific applications.
A resorbable bone wax is described in U.S. Pat. No. 5,143,730. The bone wax is asserted to be suitable for mechanical staunching of bleeding and is based on oligomers of glycolic acid and/or lactic acid monofunctional and/or polyfunctional alcohols and/or corresponding carboxylic acids.
U.S. Pat. Nos. 4,535,485 and 4,536,158 disclose certain implantable porous prostheses for use as bone or other hard tissue replacement which are comprised of polymeric materials. The disclosed prostheses are composed generally of polymeric particles. The particles have an inner core comprised of a first biologically-compatible polymeric material such as polymethylmethacrylate and an outer coating comprised of a second biologically-compatible polymeric material which is hydrophilic, such as polymeric hydroxyethylmethacrylate. The particles may incorporate a radiopaque material to render the particle visible in an X-ray radiograph. The particles may be bonded together to form a unitary structure which can be implanted in the body. Alternatively, a mass of the particles may be implanted in the body in an unbonded, granular form. In either the bonded or the unbonded form, interstices between the implanted particles form pores into which tissue can grow. Thus, the bioabsorbable particles serve as a structural support and guiding matrix for encroaching bone deposits derived from adjacent fresh bone. The hydrophilic coating on the particles facilitates infusion of body fluids into the pores of the implant, which promotes the ingrowth of tissue into the pores of the implant.
Chesterfield et al., in U.S. Pat. No. 5,697,976, disclose a porous bioabsorbable surgical implant material that is prepared by coating particles of bioabsorbable polymer with tissue ingrowth promoter. Typical bioabsorbable polymers include polymers of glycolide, lactide, caprolactone, trimethylene carbonate, dioxanone, and physical and chemical combinations thereof. The tissue ingrowth promoter can include calcium hydroxide and/or a hydrophilic coating material. The hydrophilic coating material can be bioabsorbable or non-bioabsorbable. A typical non-bioabsorbable hydrophilic coating material is polyhydroxyethyl methacrylate (PHEMA). The bioabsorbable implant material may also contain a therapeutic agent. Typical therapeutic agents include an antimicrobial agent, dye, growth factors and combinations thereof.
Medical putty for tissue augmentation is described in U.S. Pat. No. 4,595,713 and is alleged by the inventor to be useful in the regeneration of soft and hard connective tissue. As described therein, the implant material is composed of a copolymer of 60-95% epsilon caprolactone and 40-5% lactide. Catalysts used for the copolymer are metallic esters of carboxylic acids. The polymer is said to become moldable at hot water temperatures of about 115-160° F.
Rosenthal et al., in U.S. Pat. No. 5,700,476, disclose implant materials comprising a matrix structure of sponge, at least one substructure and at least one pharmacologically active agent, wherein both the matrix structure and the substructure are formed from bioabsorbable biopolymers. The substructure may, for example, comprise biopolymer films, flakes, fibres or microspheres embedded in the matrix structure of sponge. The pharmacologically active agent may comprise antiseptics, antibiotics and/or analgesics. One or more such therapeutically active agents may be incorporated separately into the matrix and/or the substructure so as to achieve controlled or phasic release of the active agents into the wound.
Great Britain Patent GB-A-2215209 describes a biodegradable, osteogenic bone-graft substitute comprising: (a) a porous, rigid structure formed from a biodegradable polymer such as polylactic or polyglycolic acid; (b) a chemotactic substance such as hyaluronic acid, fibronectin or collagen dispersed in the interstices of the rigid structure; and (c) a biologically active or therapeutic substance such as bone morphogenic protein evenly distributed throughout the volume of the bone-graft substitute. In use, the material is implanted into a bone defect. The material helps to restore functional architecture and mechanical integrity of the bone, initiate osteogenesis, and maintain the biological processes of bone growth while simultaneously being slowly bioabsorbed by the host organism.
Akalla et al., in U.S. Pat. No. 5,641,502, disclose a moldable biodegradable surgical material made of a bioabsorbable polymer derived from hydroxyacids, lactones, carbonates, etheresters, anhydrides, orthoesters and copolymers, terpolymers and/or blends thereof. The polymer is blended with at least one surface active agent selected from the group consisting of fatty acid ester and poly(oxypropylene)/poly(oxyethylene) block copolymer. In one embodiment, a leaching agent is blended with the above-mentioned surgical material. Methods of making moldable biodegradable surgical material are provided. The surgical material may be used as a moldable bone wax in connection with repair of wounds and is an adaptable aid for any appropriate surgical use, e.g., hemostat, anchor, patch etc.
The porous bioabsorbable implants that have been suggested to date are generally isotropic materials. That is to say, the structure and composition of the materials are uniform in all directions. Any pharmacological therapeutic agents are generally distributed uniformly in the biodegradable carrier materials. This, in turn, means that the active agents are released uniformly into the wound site at a rate determined only by the rate at which the implant material biodegrades and the surface area of the implant. In practice, it would be preferable to have controlled or phased release of active agents. For example, it may be desired to provide an implant having an initial rapid release of the active therapeutic agent(s) to establish a sufficient concentration of those agents at the wound surface, followed by the slower release required to maintain a constant therapeutically effective concentration. Alternatively, it may be desirable to have an initial rapid release of antiseptic followed by slower release of wound healing factors such as cytokines, EGF etc.
In open surgical procedures, it is common to apply an antibiotic, analgesic, growth stimulator, or other chemical agent at the surgical site prior to closing the incision in order to control infection, decrease pain, promote growth, etc. One of the most devastating complications of orthopaedic surgery such as total joint arthroplasty is deep sepsis. Treatment of an infected joint replacement is difficult due to its location, and localized devascularization resulting from this procedure. Current approaches to therapy for deep infections include systemic or parenteral antibiotic regimes, and the use of antibiotic-impregnated acrylic bone cement. Due to the localized devascularization, it is difficult to establish therapeutic levels of an agent in the bone surrounding the implant without exceeding toxic serum concentrations when utilizing systemic or parenteral treatments. The use of antibiotic-containing bone cement results in high local concentrations, while avoiding toxic serum levels, but the antibiotic has been shown to elute in trace quantities for extended periods of time (greater than one year). Residual trace amounts of antibiotics have raised concerns of resistant strain formation. An additional concern regarding adding antibiotics to bone cement is the possible degradation of mechanical properties of the bone cement whose primary function is as a fixation material.
According to the state of the art, it is preferable to establish and maintain therapeutic concentrations of an antibiotic at a surgical site for a period of 7 to 10 days, with no residual antibiotics lingering for extended periods of time. It is also desirable to achieve such relatively high therapeutic concentrations locally without elevating serum concentrations, thereby reducing the danger of systemic toxicity.
U.S. Pat. No. 5,681,289 to Wilcox et al. discloses a dispensing bladder for passing a low volume flow of a liquid chemical agent at an orthopaedic surgical site. The bladder is installed adjacent to or as part of an orthopaedic implant. It is coupled to a tube which receives a supply of liquid chemical such as an antibiotic via an injection port or an implanted or external reservoir and pump. The bladder may be biodegradable so as to avoid the need for extensive surgery to explant it. However, the tube, injection site, pump, and reservoir must be surgically removed. Moreover, it is believed that the delivery of a liquid antibiotic in the femoral canal may degrade the mechanical properties of bone cement on an implant stem.
In view of the limitations of prior art implantable drug delivery devices, it is desirable to provide an implantable drug delivery device in the form of a shaped plug that may be affixed to a prosthesis or a disc covering a recess in the prosthesis wherein the recess contains therapeutic agents, thereafter to biodegrade and deliver one or more therapeutic agents contained therein at a controllable rate to the surrounding tissue.